Chemical Constituents and Pharmacology of the Aristolochia ( 馬兜鈴 Mădōu Ling) Species

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Journal of Traditional and Complementary Medicine Vol. 2, No. 4, pp. 249-266 Copyright © 2011 Committee on Chinese Medicine and Pharmacy, Taiwan. This is an open access article under the CC BY-NC-ND license.

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Chemical Constituents and Pharmacology of the Aristolochia ( 馬兜鈴 mădōu ling) species

Ping-Chung Kuo1, Yue-Chiun Li1, Tian-Shung Wu2,3,4,*

1 Department of Biotechnology, National Formosa University, Yunlin 632, Taiwan, ROC 2 Department of Chemistry, National Cheng Kung University, Tainan 701, Taiwan, ROC 3 Department of Pharmacy, China Medical University, Taichung 404, Taiwan, ROC 4 Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung 404, Taiwan, ROC

Abstract Aristolochia (馬兜鈴 mǎ dōu ling) is an important genus widely cultivated and had long been known for their extensive use in traditional Chinese medicine. The genus has attracted so much great interest because of their numerous biological activity reports and unique constituents, aristolochic acids (AAs). In 2004, we reviewed the metabolites of Aristolochia species which have appeared in the literature, concerning the isolation, structural elucidation, biological activity and literature references. In addition, the nephrotoxicity of aristolochic acids, biosynthetic studies, ecological adaptation, and chemotaxonomy researches were also covered in the past review. In the present manuscript, we wish to review the various physiologically active compounds of different classes reported from Aristolochia species in the period between 2004 and 2011. In regard to the chemical and biological aspects of the constituents from the Aristolochia genus, this review would address the continuous development in the phytochemistry and the therapeutic application of the Aristolochia species. Moreover, the recent nephrotoxicity studies related to aristolochic acids would be covered in this review and the structure-toxicity relationship would be discussed.

Key words: Aristolochia, Aristolochic acid, Alkaloid, Flavonoid, Terpenoid, Bioactivity

Introduction were widely distributed in tropical, subtropical and temperate regions of the world. They are known to There are about 500 species in the genus Aristolochia occur in Asia, Africa, North and South America and and the majority of these species are distributed in the Australia but there is a wide distribution across tropical tropical region, with some exceptions range as north Asia (Liu and Lai, 1976; How, 1985; Hou, 1996). as Canada, Scandinavia, and Northern Japan. They may grow as climbing vines, as short creeping herbs Various species of Aristolochia have been used in the and a few are shrub-like (Hutchinson, 1973; Watson folk and traditional medicines as medicaments and and Dallwitz, 1992; Gonzalez, 1999). Aristolochia tonics (Andrei, 1977; Correa, 1978; Balbach, 1979; species are herbaceous perennials, undershrubs or Duke, 1985; Duke and Ayensu, 1985; Simoes et al, shrubs, often scandent, scrambling, twining, sometimes 1986; Lopes et al, 2001), especially in the traditional lianas, usually with prostrate or tuberous rhizomes or Chinese medicines (Jiangsu New Medicine College, rootstocks, and alternate, pinnate, polymorphic or lobed 1977; Li, 1977; Pharmacopeia of China, 1985; Tang leaves bearing essential oils. Species of Aristolochia and Eisenbrand, 1992; Bensky, 1993). Some species

*Correspondence to: Dr. Tian-Shung Wu. Department of Chemistry, National Cheng Kung University, Tainan 701, Taiwan, ROC, Tel: 886-6-2757575 ext 65333, Fax: 886-6-2740552, E-mail: [email protected]

249 Kuo et al. / Journal of Traditional and Complementary Medicine 2 (2012) 249-266

have been used in the form of crude drugs as anodynes, Chemical Constituents antiphlogistics, and detoxicants in Mainland China In the period between 2004 and 2011 over eighteen (Perry, 1980). In our previous review article (Wu et al, species of Aristolochia have been investigated for 2005), the purification, structural elucidation, and the chemical constituents around the world, and various biological activity of metabolites of Aristolochia species constituents have been characterized (Table 1). The have been covered and moreover the nephrotoxicity secondary metabolites from Aristolochia species cover of aristolochic acids, biosynthetic studies, ecological 16 major groups classified by their chemical structures, adaptation, and chemotaxonomy researches were also including aristolochic acids and esters, aristolactams, cited. In this present manuscript, we aimed to address aporphines, protoberberines, isoquinolines, the continuous development regarding the presences benzylisoquinolines, amides, flavonoids, lignans, of the various metabolites identified from Aristolochia biphenyl ethers, coumarins, tetralones, terpenoids, species and also their divergent bioactivities. benzenoids, steroids, and others. The aristolochic acids were host of phenanthrene derived metabolites in which the aristolactams also possessed the similar skeleton. The identified terpenoids can further be divided into three subgroups: mono-, sesqui-, and diterpenoids.

Table 1. Chemical constituents from the Aristolochia (馬兜鈴 mǎ dōu ling) species. Species Part Compound Reference A. species aristolochic acid I; aristolochic acid A (1) Chen et al, 2010a A. albida whole plant columbin (2) Nok et al, 2005 A. arcuata roots talaumidin (3) Zhai et al, 2004 Zhai et al, 2005 veraguensin (4) Zhai et al, 2005 galgravin (5) aristolignin (6) nectandrin A (7) isonectandrin B (8) nectandrin B (9) A. brevipes ground roots β-sitosterol (10) Navarro-García et al, 2011 6α-7-dehydro-N-formyl-nornantenine (11) E/Z-N-formylnornantenine (12) 7,9-dimethoxytariacuripyrone (13) 9-methoxytariacuripyrone (14) aristololactam I (15) stigmasterol (16) 3-hydroxy-α-terpineol (17) A. constricta stems aristolochic acid A (1) Zhang et al, 2008 (18) Capasso et al, 2006 (19) (20) (21) (22) (23) stems (−)-hinokinin (24) Zhang et al, 2008 9-O-[(−)-kaur-15-en-17-oxyl]cubebin (25) (−)-cubebin (26) (−)-kaur-15-en-17-ol (27) (−)-pluviatolide (28) (−)-haplomyrfolol (29) (−)-dihydrocubebin (30) 9-O-methylcubebin (31) (−)-kaur-16-en-19-oic acid (32) (−)-kauran-16α,17-diol (33)

250 Kuo et al. / Journal of Traditional and Complementary Medicine 2 (2012) 249-266

Species Part Compound Reference (−)-kaurene (34) (−)-kauran-16α,17,18-triol (35) aristololactam AII; aristolactam AII (36) cepharanone B (37) aristelegone A (38) (+)-4,7-dimethyl-6-methoxy-1-tetralone (39) cadalene (40) β-sitosterol glucoside; β-sitosteryl glucoside (41) N-trans-feruloyltyramine (42) A. contorta fruits 3"-hydroxyamentoflavone-7-O-methyl ether (43) Chen et al, 2005 3"-hydroxyamentoflavone (44) A. cretica roots aristolochic acid I; aristolochic acid A (1) Georgopoulou et al, 2005 aristolochic acid IIIa; aristolochic acid C (45) 6-O-p-coumaroyl-β-D-fructofuranosyl-(2→1)-α-D- glucopyranoside (46) arillatose B (47) 6-O-p-coumaroyl-α-D-glucopyranose (48) 6-O-p-coumaroyl-β-D-glucopyranose (49) 7-hydroxyaristolochic acid I (50) aristolochic acid II; aristolochic acid B (51) ariskanin A (52) A. cymbifera whole plant 2-oxo-populifolic acid (53) de Barros Machado et al, 2005 leaves (−)-hinokinin (24) Sartorelli et al, 2010 (−)-kusunokinin (54) (−)-copalic acid (55) (−)-fargesin (56) (+)-sesamin (57) epieudesmin (58) A. elegans stems and roots aristolochic acid I; aristolochic acid A (1) Shi et al, 2004 β-sitosterol (10) (−)-hinokinin (24) (−)-cubebin (26) (−)-kaur-15-en-17-ol (27) aristolactam AII; aristololactam AII (36) aristelegone A (38) β-sitosteryl glucoside (41) N-trans-feruloyltyramine (42) N-trans-cinnamyltyramine(54) aristolactam E (59) aristolactam-AIIIa-6-O-β-D-glucoside (60) aristoquinoline A (61) aristoquinoline B (62) aristoquinoline C (63) aristogin F (64) 9-methoxyaristolactam I (65) isoaristolactam AII (66) aristolactam AIIIa (67) aristolactam C N-β-D-glucoside (68) aristogin A (69) aristogin B (70) aristogin C (71) aristogin D (72) aristogin E (73) 4-methoxy-3,4'-oxydibenzoic acid (74) aristelegone B (75) aristelegone C (76) aristelegone D (77) pericampylinone A (78) corydaldine (79) thalifoline (80)

251 Kuo et al. / Journal of Traditional and Complementary Medicine 2 (2012) 249-266

Species Part Compound Reference northalifoline (81) N-methylcorydaldine (82) aristelegin A (83) aristelegin B (84) aristelegin C (85) α-methylcubebin (86) β-methylcubebin (87) (−)-5"-methoxyhinokinin (88) (−)-kobusin (89) (+)-medioresinol (90) aristolin (91) ent-kauran-16β,17-diol (92) ent-16β,17-epoxykauran (93) ent-15β,16-epoxykauran-17-ol (94) aristololide (95) N-cis-feruloyltyramine (96) N-p-trans-coumaroyltyramine (97) aristolochic acid IVa; aristolochic acid D (98) aristoloside (99) aristolochic acid IV methyl ester (100) methyl aristolochate; aristolochic acid I methyl ester (101) aristolochic acid D methyl ester (102) aristolochic acid Ia methyl ester (103) magnofoline; magnoflorine (104) oxonuciforine (105) isomoschatoline (106) 4,5-dioxodehydroasimilobine (107) methylparaben (108) methyl vanillate (109) p-hydroxybenzaldehyde (110) vanillin (111) methyl 4-hydroxy-3-methoxycinnamate (112) cinnamic acid (113) ω-hydroxypropioguaiacone (114) ficusol (115) A. fangchi roots aristolochic acid A; aristolochic acid I (1) Cai and Cai, 2010 aristolochic acid C; aristolochic acid IIIa (45) aristolochic acid B; aristolochic acid II (51) aristolochic acid F (116) aristolochic acid G (117) A. gigantea rhizomes β-sitosterol (10) Holzbach and Lopes, 2010 N-trans-feruloyltyramine (42) magnoflorine (104) allantoin (118) E-nerolidol (119) (+)-kobusin (120) (+)-eudesmin (121) aristolactam Ia N-β-D-glucoside (122) aristolactam Ia 8-β-D-glucoside (123) aristolactam IIIa (124) aristolactam 9-O-β-D-glucopyranosyl-(1→2)-β-D-glucoside (125) aerial stems N-trans-feruloyltyramine (42) N-p-trans-coumaroyltyramine (97) (+)-kobusin (120) trans-N-feruloyl-3-O-methyldopamine (126) N-cis-p-coumaroyl-3-O-methyldopamine (127) and N-trans-p-coumaroyl-3-O-methyldopamine (128) A. lagesiana roots (−)-(8S,8’R,9S)-cubebin (129) de Pascoli et al, 2006 (−)-(8R,8’R,9R) and (−)-(8R,8’R,9S)-cubebins (130) (8R,8’R,8’’R,8’’’R,9R,9’’S)-bicubebin A (131)

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Species Part Compound Reference A. ligesiana leaves (6R,6aS,P)-isocorydine (132) Ferreira et al, 2010 (6S,6aS,M)-isocorydine (133) (6aS,M)-(+)-norisocorydine (134) (6S,6aS,M)-(+)-corydine-N?oxide (135) (6R,6aS,P)-(+)-corydine (136) (6S,6aS,M)-corydine hydrochloride (137) and (6R,6aS,M)-corydine hydrochloride (138) lagesianine A (139) lagesianine B (140) lagesianine C (141) lagesianine D (142) glycerol (143) A. malmeana roots (−)-hinokinin (24) Messiano et al, 2008 (−)-kusunokinin (54) (−)-(8S,8’R,9S)-cubebin (129) (−)-kolavenic acid (144) leaves (−)-hinokinin (24) (−)-kusunokinin (54) (−)-copalic acid (55) (−)-fargesin (56) (−)-(8R,8’R,9R) and (−)-(8R,8’R,9S)-cubebins (130) (−)-ent-6-β-hydroxycopalic acid (145) (−)-phillygenin (146) (−)-2-oxokolavenic acid (147) A. manshuriensis stems aristolochic acid I; aristolochic acid A (1) Chung et al, 2011 aristolochic acid IIIa; aristolochic acid C (45) aristolochic acid IVa; aristolochic acid D (98) aristolochic acid-I methyl ester; methyl aristolochate (101) aristolactam IIIa (124) aristopyridinone A (148) aristolamide (149) aristolamide II (150) aristolic acid methyl ester (151) 6-methoxyaristolic acid methyl ester (152) A. pubescens roots and stems aristolochic acid A; aristolochic acid I (1) Nascimento et al, 2003 (−)-cubebin (26) (−)-kaur-15-en-17-ol (27) (+)-sesamin (57) (+)-eudesmin (121) tubercula (−)-(8S,8’R,9S)-cubebin (129) de Pascoli et al, 2006 (−)-(8R,8’R,9R) and (−)-(8R,8’R,9S)-cubebins (130) (8R,8’R,8’’R,8’’’R,9R,9’’S)-bicubebin A (131) A. ridicula leaves ridiculuflavone A (153) Machado and Lopes, 2005 ridiculuflavone B (154) ridiculuflavonylchalcone A (155) proto-quercitol (156) ridiculuflavone C (157) Machado and Lopes, 2008 ridiculuflavone D (158) ridiculuflavonylchalcone B (159) ridiculuflavonylchalcone C (160) A. tagala roots kaempferol (161) Battu et al, 2011 A. taliscana roots licarin A (162) León-Díaz et al, 2010 licarin B (163) eupomatenoid-7 (164)

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Aristolochic acids and esters of aristolochic acid were reported from the Aristolochia The constituents from the Aristolochia genus species and among these only ariskanin A (52) did not became the interesting topic for the phytochemical possess the 3,4-methylenedioxy substitution pattern. and pharmaceutical researchers since the discovery of Only few cases of aristolochic acid esters, including aristolochic acid derivatives. The naturally occurring aristolic acid methyl ester (151) and 6-methoxyaristolic aristolochic acids possessed the 3,4-methylenedioxy- acid methyl ester (152), do not possess the nitro 10-nitro-phenanthrenic-1-acid skeleton are typical group at the C-10 position. The majority of these constituents of the Aristolochia species and claimed denitroaristolochic acids were reported from the to be responsible for the various biological activity of Formosan A. manshuriensis (Chung et al, 2011). Aristolochia species. Figure 1 lists the eight aristolochic acids that have been characterized from Aristolochia. Aristolactams Aristolactams are regarded as biogenetic intermediates Aristolochic acid I (1) is the most abundant aristolochic in the biosynthetic pathway of aristolochic acids. acid found in almost all species of Aristolochia studied They are usually supposed to originate from the with few exceptions. However, the main concern of cyclization condensation reaction of the reduction recent studies has focused on the negative aspects of products of aristolochic acids. From Figure 2, it is aristolochic acids due to the Chinese Herb Nephropathy evident that twelve aristolactams have been reported (Cosyns, 2003). Recently health food supplements from Aristolochia species and among them there were containing aristolochic acids have been prohibited for also six compounds having the 3,4-methylenedioxy use in weight reduction with complete scientific results substitution groups. Aristolactam I (15), aristolactam supported (The European Agency for the Evaluation AII (36), and aristolactam Ia N-β-D-glucoside (122) of Medicinal Products, 1997; Therapuetic Goods were the frequently encountered aristolactams in the Administration, 2001). In addition, seven methyl esters Aristolochia species. Aristolactam II (36) found in COOH COOCH O O 3 several species of Aristolochia is a simple aristolactam without any substitutions on rings B and C. The NO2 R4 O O 9-oxygenated aristolactams are rare in Aristolochia with only compounds 68 and 125 being reported. Compound 125 was one example of 9-oxygenated aristolactam with the substitution of diglucoside.

R3 R1 R6 R5

R2 O R4 R5 R6 R1 R2 R3 R2O 100 NO2 OCH3 OCH3 1 OCH3 HH 101 NO OCH H 45 H H OH 2 3 102 NO2 OCH3 OH N R3 50 OCH3 OH H 103 NO OHH 51 HHH 2 151 H OCH3 OCH3 98 OCH3 H OH R1O 152 H OCH3 H 99 OCH3 Glc H 116 H OH H 117 OH H OH R4

O R7 R5

R H3CO 6

OCH3 R1 R2 R3 R4 R5 R6 R7 15 CH2 H H OCH3 HH NO2 36 CH3 HHHHHH H3CO 37 CH3 CH3 HHHHH 59 H CH3 H H OH OCH3 H 60 CH3 H H H H H OGlc 66 H CH3 HHHHH 67 CH3 H H H H H OH 68 CH2 Glc OCH3 OCH3 H OH 122 CH2 Glc H OH H H 123 CH2 H H Glc H H 124 CH2 H H H H OH 52 125 CH2 H OGlc-Glc OCH3 HH

Figure 1. Aristolochic acids and esters from the Aristolochia species. Figure 2. Aristolactams from the Aristolochia species.

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Aporphines of the precursors of aristolactams and aristolochic Seventeen aporphine alkaloids have been characterzied acids in plants. Only 4,5-dioxodehydroasimilobine from Aristolochia species (Figure 3). Aporphines (107) was reported from A. elegans (Shi et al, 2004). with N -formyl substitution, 6α,7-dehydro-N - Most of the aporphines found in Aristolochia species formylnornantenine (11) and N-formylnornantenine possess 4,5-tetrahydro basic skeleton. Lagesianines (12), were reported from A. brevipes (Navarro-García et B-D (140-142) were the dimeric aporphine alkaloids al, 2011). The polar quaternary aporphine magnoflorine linked through the substituent on nitrogen, oxygenated (104) was found in A. elegans and A. gigantea. The functions, and substituent on the phenanthrene ring, 4,5-dioxoaporphine is a small group of aporphine respectively. These dimeric aporphines were only alkaloid found mostly among the Aristolochiaceae reported from the leaves of A. ligesiana (Ferreira et al, family and usually considered as possible intermediates 2010).

H3CO R1

H3CO H CO 3 N HO R 1 H3CO N O H N H3CO H3CO H3CO R2 H N H HO HO H CO 3 HO

R1 O H3CO O CH3 R R 1 2 135 H CO O- 3 H CH 11 132 3 6Į,7 136 CH3 12 ǻ 133 H CH3 104 H Cl- 134 H H 139 137 OH CH3 CH3

CH3 138 H Cl-

- R1 O Cl Cl- H3CO OCH3 H3CO HO O

N N OCH N NH H3CO 3 H H H H H3CO H CO 3 HO OH

H3CO OCH3

140 105 R = H 1 107 106 R1 = OH

H3CO

H CO 3 NH H3CO OH H Cl- - N Cl H O HO OCH3 N OCH HO 3 OH HN OH H3CO OCH3 2HCl OH H3CO

OCH3

142 OCH3 141 Figure 3. Aporphines from the Aristolochia species.

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R1O H3CO

N N H3CO R1 O CO2H H R2

18 R1 = CH3,R2 = CH3 5,6 19 R1 = CH3,R2 = CH3, ǻ 5,6 20 R1 = H, R2 = H, ǻ OR2 21 R1 = H, R2 = H O 22 R1 = CH3,R2 = H

OR3 H3CO R1 R2 R3 61 CH3 O CH3 N 62 O CH3 CH3 H3CO 63 O CH3 H

OH Figure 6. Benzylisoquinolines from the Aristolochia species.

OH Benzylisoquinolines

23 The occurrence of benzylisoquinoline type alkaloids, Figure 4. Protoberberines from the Aristolochia species. aristoquinolines A-C (61-63) constitute the first report of N-oxide benzoyl benzyltetrahydroisoquinoline ether alkaloids from Aristolochia species (Figure 6). These Protoberberines provided the natural evidence for the catabolic process Occurrence of protoberberine alkaloids (Figure of structurally interesting bisbenzyltetrahydroisoquinol 4) was rare in Aristolochia , and they were only ines. The isoquinolones, benzylisoquinolines, biphenyl reported from A. constricta (Capasso et al, 2006). ethers, and N-oxide benzoyl benzyltetrahydroisoqu 8-Benzyltetrahydroprotoberberine type alkaloid, 23, had inoline ether alkaloids were derived biogenetically been obtained by introduction of a benzyl group at C-8 from bisbenzylisoquinolines, common metabolites of berberine to result in this unusual carbon skeleton. of Aristolochia species, in general alkaloid catabolic process (Shi et al, 2004). Isoquinolines The presence of isoquinoline alkaloids 78-82 Amides in the genus Aristolochia is limited to A. elegans. The amides are another type of compounds isolated Purified compounds of this class were listed in the from several Aristolochia plants (Figure 7). One class Figure 5. All of these alkaloids reported possessed the of the amides from Aristolochia species, on structural tetrahydroisoquinolone basic skeleton. Isoquinoline investigation were found to contain a tyramine unit alkaloids were usually considered as biogenetic connected to phenolic acids like cis- or trans- coumaric intermediates in the catabolic process of bisbenzyl- and ferulic acids. Aristolamide (149) and aristolamide tetrahydroisoquinoline alkaloids (Shi et al, 2004). II (150) isolated from A. manshuriensis (Chung et al,

2011) contain –CONH2 group at C-1 which possessed the phenanthrene basic skeleton was another class of amide reported from Aristolochia species. R2O

Flavonoids N Flavonoids continue to attract the researchers’ R O R 3 1 interests due to their structural diversity, biological and O ecological significance. They affect plant interactions with microsymbionts (Romeo et al, 1998), insect

R1 R2 R3 predators and pollinators (Harborne, 1986; Stafford, 78 HHH 1997), and also function in pigmentation and act as 79 H H CH3 80 CH3 H CH3 protectants against UV irradiation (Brouillard, 1988; 81 H CH3 H 82 CH3 CH3 CH3 Ylstra et al, 1992; Harborne, 1994). Virtually almost Figure 5. Isoquinolines from the Aristolochia species. all higher plants produce flavonoids, however, some

256 Kuo et al. / Journal of Traditional and Complementary Medicine 2 (2012) 249-266

OH OH R3 O

R1 N R2 HO O N R4 H H

HO R1 R2 R3 R4 42 OCH3 H 96 OCH3 H 97 HH 127 H OCH3 126 OCH3 OCH3 O 128 H OCH3

O H NH2 N OH O O O HN O HN

N H NH2 O OH 118 148 R5 149 R5 = OCH3 150 R5 = H Figure 7. Amides from the Aristolochia species.

OH H3CO OCH3

HO O O OH OH O HO OH O O OH O O O OCH3 H3CO OH O O O 161

H3CO OCH3 155 HO OH OR3

R2O O OCH3 OH OH

H CO O OR1 O 3 O HO O OCH OR4 3 O OH O

OH HO R1 R2 R3 R4 153 HHHH OH 154 H CH3 HH 159 157 CH3 H CH3 CH3 158 H CH3 HH OH OCH3 OH

H3CO O O

OCH3 OH OH O OH O O R1O O OH O O O OH

HO OH HO O OCH3 OH O O OH H3CO 43 R = CH3 44 R = H

O OH 160

Figure 8. Flavonoids from the Aristolochia species.

257 Kuo et al. / Journal of Traditional and Complementary Medicine 2 (2012) 249-266

OCH O 3 H3CO OCH3 H3CO OCH3 O H3CO OCH3 O O O

O OH H3CO OCH3 H3CO OCH3 HO OCH3

3 4 5 6

H CO OCH 3 3 H3CO OCH3 H3CO OCH3 O O O

HO OCH3 HO OH HO OH 7 8 9

O H O R OH O H 3 OH R1 R2 R3 R4 R5 R6 O R2O O 24 CH2 =O H CH2 26 CH OH H CH O O 2 2 H 28 H CH3 =O H CH2 R1O 29 H CH3 H OH CH2 H R4 31 CH2 H OCH3 CH2 54 CH2 =O H CH3 CH3 O OCH 83 CH2 =O OCH3 CH2 O 3 O 86 CH2 OCH3 H CH2 O 87 CH2 OCH3 H CH2 R5O 30 88

OR6

R3 H OH R1O H O OCH O R 3 O 1 R O O 2 O O H OH H R2 OCH3 OCH3

R R H3CO 1 2 164 162 OCH3 H OCH3 O 163 OCH2O O R R R 1 2 3 R5 84 CH CH OH 3 3 129 85 CH2 OH OR3 O OCH3 OR4 OR1 H H O O OCH3 R2O OR O 2 H H H H H3CO R1O H3CO O O R1 R2 R3 R4 R5 H CO 3 57 CH2 CH2 H H3CO 90 H CH3 H CH3 OCH3 R R 120 CH2 CH3 CH3 H 1 2 58 121 CH CH CH CH H 56 CH2 3 3 3 3 146 H CH3

H O H

OH O O O O

O O O OCH3 H H H H

O O O O O O O 89 131

Figure 9. Lignans from the Aristolochia species.

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of them are fairly unique, in which many specific OR1 compounds are accumulated during plant growth and O O development. Six bisflavones, one unusual chalcone- H CO CO H flavone dimer and two tetramers were characterzied R3 3 2 R CO2H from A. ridicula (Machado and Lopes, 2005; 2008) 2 (Figure 8). These reports constitute the presence of bi- R1 R2 R3 74 64 CH3 CO2H CH2OH and tetraflavonoids in the family Aristolochiaceae. In 69 CH3 CHO CO2CH3 70 CH3 CO2CH3 CHO addition, there was also simple flavone reported from 71 CH3 CO2CH3 CO2CH3 Figure 10. Biphenyl ethers from the 72 H CO2CH3 CO2CH3 Aristolochia species, like kaempferol (161) from A. 73 CH3 CO2CH3 CH2OH Aristolochia species. tagala (Battu et al, 2011).

Lignans Coumarins Lignans were another important type of metabolites Although there were only two coumarins, 7,9-dimeth found in several species of Aristolochia. There are oxytariacuripyrone (13) and 9-methoxytariacuripyrone five basic skeletons of neolignans and lignans with (14), characterized from the roots of A. brevipes structural diversity reported from Aristolochia genus (Figure 11), these constituents also displayed significant (Figure 9), including diaryldimethyltetrahydrofuranoids, physiological activity (Navarro-García et al, 2011). dibenzylbutanoids, benzofurans, and bisepoxylignans. Tetralones The 2,5-diaryl-3,4-dimethyl- tetrahydrofuranoids 3-9 Among five tetralones reported from Aristolochia were all characterized from the roots of A. arcuata (Zhai species so far (Figure 12), four tetralones, aristelegones et al, 2004; 2005). Occurrence of the dibenzylbutane A-D (38, 75-77) have been characterized in the stems type lignans is the most common in Aristolochia and roots of A. elegans collected in Taiwan (Shi et genus. These lignans could be further divided into al, 2004). Aristelegone A (38) and (+)-4,7-dimethyl- dibenzyltetrahydrofurans, dibenzylbutyrolactones, and 6-methoxy-1- tetralone (39) were reported from the dibenzylbutane diol depending on their oxidation states. stems of A. constricta (Zhang et al, 2008). Most of Licarin A (162), licarin B (163), and eupomatenoid-7 these identified tetralones possessed a keto substituent (164) were benzofuran type lignans only reported from at C-1 except that aristelegone D (77) had 1,2-diol A. taliscana (León-Díaz et al, 2010). The other type of functionalities. lignans frequently encountered in Aristolochia species were the bisepoxylignans which were exemplified in Figure 9, reported from A. cymbifera, A. elegans, A. R1 gigantea, and A. malmeana, respectively. In addition, there was also one dimeric lignan (8R, 8'R, 8''R, 8'''R, R2 9R, 9''S)-bicubebin A (131) linked through the oxygen O O atom (de Pascoli et al, 2006).

Biphenyl ethers OCH3

Seven biphenyl ethers had been reported, including 13 R1 = OCH3,R2 = OCH3 14 R = NO ,R = H aristogins A-E (69-73), F (64), and 4-methoxy- 1 2 2 3,4-oxydibenzoic acid (74) (Figure 10). All these Figure 11. Coumarins from the Aristolochia species. compounds have only been reported from A. elegans R (Shi et al, 2004) and they are usually considered as 2 CH3 one of the end products in the catabolic process of R 3 H3CO bisbenzylisoquinoline alkaloids.

R R 4 1 H3C OH

O OH

R1 R2 R3 R4 38 H CH3 OH CH3 77 39 H CH3 OCH3 CH3 75 OH CH3 OCH3 CH3 76 H CH3 OH CH2OH

Figure 12. Tetralones from the Aristolochia species.

259 60Kuo et al. / Journal of Traditional and Complementary Medicine 2 (2012) 249-266

O H H OH

OCOCH3 OH H OH H H 119

17 40 95 O

H H O OH OH O OH H O H H

O O O O O O CH3

53 144 147 CH3 OH

H H

OH OH OH H O H O

H OH H COOH

55 145 27 32

H H H H OH OH OH OH OH H H OH H H H H OH H H

35 92 33 34

CH OH H 2

H O O H O O H H O H O H O 93 C O H NO2 O O

OH O 25 H O

H OCH3

94 91

Figure 13. Terpenoids from the Aristolochia species.

260 Kuo et al. / Journal of Traditional and Complementary Medicine 2 (2012) 249-266

R1 Terpenoids O

R2 Although there were so many terpenoids characterized R5 OR6 from Aristolochia species in our previous review (Wu et al, 2005), the number of terpenoids reported in the R4 period between 2004 and 2011 was comparatively R3 R4 R5 R6 R1 R2 R3 112 OH OCH CH limited (Figure 13). Only one monoterpene, 3-hydroxy- 108 OH H CO CH 3 3 2 3 113 HHH 109 OH OCH3 CO2CH3 α-terpineol (17), was identified from the roots of 110 OH H CHO 111 OH OCH3 CHO A. brevipes (Navarro-García et al, 2011). Three sesquiterpenoids, cadalene (40) (Zhang et al, 2008), O aristololide (95) (Shi et al, 2004), and E-nerolidol (119) H CO2CH3 H3CO H3CO OH (Holzbach and Lopes, 2010), belonged to the cadinane, OH bourbonanes, and farnesane basic skeleton, respectively, HO HO were also characterized from the Aristolochia species. 114 115 The diterpenoids with three types of C20 carbon skeletons constitute the largest group of terpenoid R7 metabolites in Aristolochia. First type of diterpenoid is the clerodane basic skeleton. 2-Oxo-populifolic HO O HO acid (53) was reported from A. cymbifera and O O HO O Fruc = (−)-kolavenic acid (144) and (−)-2-oxokolavenic acid HO HO OH

(147) were purified from A. malmeana, respectively. CH3 OH R8

A furanolactone diterpene belonged to the clerodane R7 R8 46 H Į-O-Fruc type was isolated from the rhizomes of A. albida (Nok 47 OH Į-O-Fruc 48 H Į-OH et al, 2005) and identified as columbin (2). Second type 49 H ȕ-OH is labdanes in which only (−)-copalic acid (55) and Figure 14. Benzenoids from the Aristolochia species. (−)-ent-6-β-hydroxycopalic acid (145) possessed this basic skeleton that were only a little different from the clerodane type diterpenoids. From the reports up to date, H H OH it revealed that Aristolochia species were rich sources H HO OH of ent-kaurane diterpenoids. In our reviewing period, H totally eight ent-kaurane diterpenoids were reported HO H H from A. constricta , A. elegans , and A. pubescens . OH RO HO OH In addition, one ent-kaurane lignan 9-O-[(−)-kaur- OH 156 10 R = H 15-en-17-oxyl]cubebin (25), and one ent -kaurane 16 R = H, ǻ22,23 41 R = Glc 143 diterpenoid ester of aristolochic acid aristolin (91) were also characterized from A. constricta and A. elegans, Figure 15. Steroids and others from the Aristolochia species. respectively. Aristolin (91) is the first example of an ester composed of aristolochic acid and a diterpenoid, in which C-16 hydroxy group of ent-kauran-16-β, 17-diol are ferulic, cinnamic, p-coumaric, and caffeic acids involves in the ester linkage with C-11 carboxylic acid derivatives. group of aristolochic acid (Shi et al, 2004). Steroids and others Benzenoids Steroids are usually encountered in natural sources, A number of benzenoid derivatives were isolated and those presented in Aristolochia species are mostly from different Aristolochia species, which include derivatives of β-sitosterol and stigmasterol. Among phenylmethanoids and phenylpropanoids (Figure these steroids, β-sitosterol (10) and β-sitosteryl 14). Four simple benzenoid derivatives 108-111 were glucoside (41) were frequently found in several isolated from the stems and roots of A. elegans (Shi et Aristolochia species (Figure 15). In addition, some al, 2004). Eight phenylpropanoids, including aglycones miscellaneous compounds including glycerol (143) 112-115 from A. elegans and glycosides 46-49 from A. and proto-quercitol (156) were also reported from cretica, respectively, were reported and most of them Aristolochia species.

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Pharmacology Table 2. Bioactivity of the crude extracts of the Aristolochia (馬兜鈴 mǎ dōu ling) species. There were a lot of worthy achievements related to Source Parts Bioactivity Reference the pharmacology of Aristolochia to be published to A. baetica stem insecticidal Jbilou et al, 2008 evidence the extensive use of Aristolochia species in roots antiproliferative Chaouki et al, 2010 folk/traditional medicines. The aristolochic acids have A. bracteolata whole antiplasmodial Ahmed et al, been considered to be the most potent fraction of the plant antiallergic 2010 Chitme et al, Aristolochia constituents. Aristolochic acid I, the most 2010 active constituent of Aristolochia has been used for leaves antifeedant Elango et al, medicinal purposes since the Graeco-Roman period. 2011 A. brevipes ground antimycobacterial Navarro-García However, following the observations that the compound roots et al, 2011 was mutagenic and carcinogenic, it was removed from A. constricta stems antispasmodic Zhang et al, pharmaceutical products since a decade (Pharmacopoeia 2008 A. cymbifrea whole antimicrobial de Barros of the People’s Republic of China, 1977). Various plant Machado et al, bioactivity studies have been reported to assess the 2005 traditional uses of Aristolochia species and these results stems antibacterial Alviano et al, 2008 were summarized in Table 2. Some of the Aristolochia A. elegans roots and anti scorpion Izquierdo et al, species, including A. baetica , A. bracteolata , A. aerial venom 2010 part indica, A. malmeana, and A. pubescens, have been roots anti scorpion Jiménez-Ferrer reported to exhibit insecticidal and repellent activities. venom et al, 2005 The crude extracts of A. brevipes, A. cymbifrea, A. A. indica roots antibacterial Kumar et al, 2006 indica, A. mollissima, and A. taliscana also display antifungal Kumar et al, significant antimicrobial activities. The phytochemical 2006 compositions and pharmacology of Aristolochia genus leaves anti snake venom Samy et al, 2008 have evoked a great deal of interest due to their multiple leaves mosquito- Kamaraj et al, adulticidal 2010 traditional uses and various bioactivity reports on their mosquito- Kamaraj et al, crude extracts. Therefore, Aristolochia become one of repellent 2010 mosquito- Kamaraj et al, the intensely investigated genera and a large number larvicidal 2010 of papers have been published on the production of A. malmeana roots insecticidal Messiano et al, physiologically important metabolites by Aristolochia. 2008 A. mollissima rhizome antimicrobial Yu et al, 2007 The divergent bioactivities reports of the compounds and aerial identified from the Aristolochia species was listed in part Table 3. It was famous that in the previous studies A. pubescens roots and insecticidal Nascimento et stems al, 2003 aristolochic acid I (1) exhibited significant cytotoxicity A. tagala roots antiinflammatory Battu et al, 2011 thus aristolochic acid I (1) (Chen et al, 2010a), (syn: A. aristolochic acid-IVa (98), aristolactam IIIa (124), and acuminata) A. taliscana roots antimycobacterial León-Díaz et al, aristolamide II (150) (Chung et al, 2011) were examined 2010 for their anti-inflammatory potentials and displayed significant effects. The lignans purified from A. anti-addictive effects and these results indicated that arcuata, talaumidin (3), galgravin (5), aristolignin (6), the alkaloids were able to produce significant influence nectandrin A (7), isonectandrin B (8), and nectandrin on the opiate withdrawal in vitro and these compounds B (9) all exhibited neuroprotective bioactivity (Zhai et were able to exert their effects both at μ and κ opioid al, 2005). In addition, (−)-hinokinin (24), (−)-cubebin agonists (Capasso et al, 2006). (26), (−)-pluviatolide (28), and (−)-haplomyrfolol (29) Licarin A (162), licarin B (163), and eupomatenoid-7 from A. constricta also displayed antispasmodic activity. (164) reported from A. taliscana (León-Díaz et There was also one diterpenoid, (−)-kaur-16-en-19- al, 2010); and 7,9-dimethoxytariacuripyrone (13), oic acid (32) to show the antispasmodic effect (Zhang 9-methoxytariacuripyrone (14), and aristololactam I et al, 2008). A. constricta is a medicinal plant found in (15) from A. brevipes (Navarro-García et al, 2011) were Ecuador and widely distributed in South America. The examined for their antimycobacterial effects and the protoberberines 18-21 from A. constricta exhibited the results confirmed their potentials indicated in the crude

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extracts. Mycobacterium tuberculosis (MTB) is one of and hexane extracts of A. taliscana possesses strong in the species of the so-called tuberculosis complex and is vitro antimycobacterial activity against Mycobacterium the causative agent of tuberculosis (TB). The increase tuberculosis strains. Among the tested compounds, in the number of cases of TB has been associated with licarin A (162) was the most active compound, with the infection of humans with HIV, in addition to the minimum inhibitory concentrations (MICs) of 3.12-12.5 appearance and development of TB-resistant drugs, both μg/mL against the following M. tuberculosis strains: multidrug-resistant (MDR), as well as extremely drug- H37Rv, four mono-resistant H37Rv variants and 12 resistant (XDR). These studies demonstrated that the clinical MDR isolates, as well as against five non- dichloromethane extracts of rhizomes of A. brevipes tuberculous mycobacteria (NTM) strains.

Table 3. Bioactivity of the compounds identified from theAristolochia (馬兜鈴 smǎ dōu ling) species. Compound Source Bioactivity Reference aristolochic acid I (1) antiinflammatory Chen et al, 2010a A. constricta antispasmodic Zhang et al, 2008 A. pubescens insecticidal Nascimento et al, 2003 A. fangchi antiplatelet Shen et al, 2008 aristolochic acid A (1) A. fangchi cytotoxic Cai and Cai, 2010 columbin (2) A. albida trypanocidal Nok et al, 2005 antitrypanosomal talaumidin (3) A. arcuata neurotrophic Zhai et al, 2004 Zhai et al, 2005 neuroprotective Zhai et al, 2005 galgravin (5) A. arcuata neurotrophic Zhai et al, 2005 aristolignin (6) A. arcuata neurotrophic Zhai et al, 2005 nectandrin A (7) A. arcuata neurotrophic Zhai et al, 2005 neuroprotective isonectandrin B (8) A. arcuata neurotrophic Zhai et al, 2005 neuroprotective nectandrin B (9) A. arcuata neurotrophic Zhai et al, 2005 neuroprotective 7,9-dimethoxytariacuripyrone (13) A. brevipes antimycobacterial Navarro-García et al, 2011 9-methoyitariacuripyrone (14) A. brevipes antimycobacterial Navarro-García et al, 2011 aristololactam I (15) A. brevipes antimycobacterial Navarro-García et al, 2011 (18) A. constricta anti-addictive Capasso et al, 2006 (19) A. constricta anti-addictive Capasso et al, 2006 (20) A. constricta anti-addictive Capasso et al, 2006 (21) A. constricta anti-addictive Capasso et al, 2006 (−)-hinokinin (24) A. constricta antispasmodic Zhang et al, 2008 A. cymbifera antitrypanosomal Sartorelli et al, 2010 (−)-cubebin (26) A. constricta antispasmodic Zhang et al, 2008 (−)-kaur-15-en-17-ol (27) A. pubescens insecticidal Nascimento et al, 2003 (−)-pluviatolide (28) A. constricta antispasmodic Zhang et al, 2008 (−)-haplomyrfolol (29) A. constricta antispasmodic Zhang et al, 2008 (−)-kaur-16-en-19-oic acid (32) A. constricta antispasmodic Zhang et al, 2008 (−)-kusunokinin (39) A. malmeana insecticidal Messiano et al, 2008 aristolochic acid II (51) A. fangchi antiplatelet Shen et al, 2008 2-oxo-populifolic acid (53) A. cymbifera antimicrobial de Barros Machado et al, 2005 (−)-kusunokinin (54) A. cymbifera antitrypanosomal Sartorelli et al, 2010 (−)-copalic acid (55) A. cymbifera antitrypanosomal Sartorelli et al, 2010 (−)-fargesin (56) A. cymbifera antitrypanosomal Sartorelli et al, 2010 (+)-sesamin (57) A. cymbifera antitrypanosomal Sartorelli et al, 2010 epieudesmin (58) A. cymbifera antitrypanosomal Sartorelli et al, 2010 (+)-eudesmin (82) A. pubescens insecticidal Nascimento et al, 2003 aristolochic acid IVa (98) A. manshuriensis antiinflammatory Chung et al, 2011 (+)-sesamin (121) A. pubescens insecticidal Nascimento et al, 2003 aristolactam IIIa (124) A. manshuriensis antiinflammatory Chung et al, 2011 cyclin-dependent kinase inhibiting Hegde et al, 2010 aristolamide II (150) A. manshuriensis antiinflammatory Chung et al, 2011 kaempferol (161) A. tagala antiinflammatory Battu et al, 2011 licarin A (162) A. taliscana antimycobacterial León-Díaz et al, 2010 licarin B (163) A. taliscana antimycobacterial León-Díaz et al, 2010 eupomatenoid-7 (164) A. taliscana antimycobacterial León-Díaz et al, 2010

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Chagas disease is a chronic illness caused by the specific biomarker of exposure, and are found also flagellate protozoan Trypanosoma cruzi , and it is in the urothelium, where they give rise to a unique the major cause of morbidity and mortality in many mutational signature in the TP53 tumor-suppressor gene. regions of South America. A. cymbifera has been From the research results, it could be concluded that used in traditional medicine as an abortifacient and exposure to aristolochic acid contributed significantly an emmenagogue as well as in the treatment of fever, to the incidence of UUC, a finding with significant diarrhea, and eczema. The experimental results of implications for global public health (Chen et al, 2012). purification of A. cymbifera and bioactivity study demonstrated that (−)-kusunokinin (54) and (−)-copalic Conclusion acid (55) were the most active compounds against This review of literature including phytochemical and trypomastigotes of T. cruzi. Additionally, (−)-copalic pharmacological investigations on Aristolochia species acid (55) demonstrated the highest parasite selectivity have covered 164 compounds belonged to the classes of as a result of low toxicity to mammalian cells, despite a aristolochic acids and esters, aristolactams, aporphines, considerable hemolytic activity at higher concentrations. protoberberines, isoquinolines, benzylisoquinolines, Among the isolated compounds, (−)-kusunokinin (54) amides, flavonoids, lignans, biphenyl ethers, coumarins, could be considered the most promising candidate, as tetralones, terpenoids, benzenoids, steroids, and others it displayed significant activity against intracellular with extensive physiological activities. Recently, amastigotes and trypomastigotes without hemolytic the focus of the pharmacology of the Aristolochia activity (Sartorelli et al, 2010). species was mainly on the nephrotoxic aristolochic acids responsible for a tragic disease of Chinese herb Nephrotoxicity nephropathy recognized in 1992. It may thus be of Chinese herbs nephropathy (CHN) is a rapidly more than academic interest to examine the remaining progressive interstitial nephropathy reported after the Aristolochia plants for their aristolochic acid presence introduction of Chinese herbs in a slimming regimen to prevent the issues like Chinese herb nephropathy followed by young Belgian women (Vanherweghem et and Balkan endemic nephropathy. This review will al, 1993; Nortier et al, 2000). Because of manufacturing help researchers and scientists in locating the detailed error, there were several reports on the adverse effects information on Aristolochia species and address the of this slimming regimen. Firstly, in 1992, some cases continuous development in the phytochemistry and the of women presenting with a rapidly progressive renal therapeutic application of the Aristolochia species in the failure after having followed a slimming regimen period between 2004 and 2011. including powdered extracts of Chinese herbs, one of them being Stephania tetrandra were recorded. This Acknowledgement outbreak of renal failure eventually resulted in about Authors are grateful for the financial support of the 100 cases in 1998, 70 % of them being in end-stage grants from the National Science Council, Taiwan, renal disease (ESRD) (Vanherweghem, 2002). Chinese Republic of China. herbs nephropathy is characterized by early, severe anemia, mild tubular proteinuria and initially normal References arterial blood pressure in half of the patients (Cosyns, 2003). The recent studies have confirmed that the main Ahmed, E.H.M., Nour, B.Y.M., Mohammed, Y.G., Khalid, H.S., 2010. Antiplasmodial activity of some medicinal plants used in Sudanese culprit leading to renal injury is aristolochic acid found folk-medicine. Environmental Health Insights 4, 1–6. in many Chinese herbal preparations (Balachandran et Alviano, W.S., Alviano, D.S., Diniz, C.G., Antoniolli, A.R., Alviano, C.S., Farias, L.M., Carvalho. M.A.R., Souza, M.M.G., Bolognese, al, 2005; Nedelko et al, 2009; Chen et al, 2010b; Zhu et A.M., 2008. In vitro antioxidant potential of medicinal plant al, 2010; Chen et al, 2012). Aristolochic acid, a potent extracts and their activities against oral bacteria based on Brazilian human carcinogen produced by Aristolochia plants, folk medicine. Archives of Oral Biology 53, 545–552. Andrei, Ed. 1977. Farmacopeia homeopatica Brasileira, Sao Paulo. is associated with urothelial carcinoma of the upper Balachandran, P., Wei, F., Lin, R.C., Khan, I.A., Pasco, D.S., 2005. urinary tract (UUC). Following metabolic activation, Structure activity relationships of aristolochic acid analogues: toxicity in cultured renal epithelial cells. Kidney International 67, aristolochic acid reacts with DNA to form aristolactam 1797–1805. (AL)-DNA adducts. These lesions concentrate in Balbach, A. 1979. Flora nacional na medicina domestica, 11th Ed., the renal cortex, where they serve as a sensitive and Edel, Sao Paulo, pp. 45, 458, 573, 739, 840. Battu, G.R., Parimi, R., Shekar, K.B.C., 2011. In vivo and in vitro

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pharmacological activity of Aristolochia tagala (syn: Aristolochia Acretoside, a new sucrose ester from Aristolochia cretica. Journal acuminate) root extracts. Pharmaceutical Biology 49, 1210–1214. of Asian Natural Products Research 7, 799–803. Bensky, D., Gamble, A., Kaptchuk, T., and Bensky, L.L. 1993. Gonzalez, F. 1999. A phylogenetic analysis of the Aristolochioideae Chinese herbal medicine: materia medica, revised Ed., Eastland (Aristolochiaceae), Ph. D thesis, The City University of New York. Press, Seattle, p. 136. Harborne, J.B. 1986. Plant flavonoids in biology and medicine: Brouillard, R. 1988. The flavonoids – advances in research since 1980, biochemical, pharmacological, and structure-activity relationships, Chapman and Hall, New York, p. 525. in Cody, V., Middleton, E. Jr., Harborne, J.B. eds, Progress in Cai, Y., Cai, T.G., 2010. Two new aristolochic acid derivatives from clinical and biological research, Alan R. Liss, New York, p. 15. the roots of Aristolochia fangchi and their cytotoxicities. Chemical Harborne, J.B. 1994. The flavonoids – advances in research since and Pharmaceutical Bulletin 58, 1093–1095. 1986, Chapman and Hall, London. Capasso, A., Piacente, S., Tommasi, N.D., Rastrelli, L., Pizza, C., Hegde, V.R., Borges, S., Patel, M., Das, P.R., Wu, B., Gullo, V.P., 2006. The effect of isoquinoline alkaloids on opiate withdrawal. Chan, T.M., 2010. New potential antitumor compounds from Current Medicinal Chemistry 13, 807–812. the plant Aristolochia manshuriensis as inhibitors of the CDK2 Chaouki, W., Leger, D.Y., Eljastimi, J., Beneytout, J.L., Hmamouchi, enzyme. Bioorganic & Medicinal Chemistry Letters 20, 1344– M., 2010. Antiproliferative effect of extracts from Aristolochia 1346. baetica and Origanum compactum on human breast cancer cell line Holzbach, J.C., Lopes, L.M.X., 2010. Aristolactams and alkamides of MCF–7. Pharmaceutical Biology 48, 269–274. Aristolochia gigantea. Molecules 15, 9462–9472. Chen, Y.G., Yu, L.L., Huang, R., Liu, J.C., Lv, Y.P., Zhao, Y., 2005. Hou, D. 1996. Flora of Taiwan, 2nd Ed., Vol. 2, Editorial Committee 3"-Hydoxyamentoflavone and its 7-O-methyl ether, tow new of the Flora of Taiwan, Taipei, pp. 636–642. biflavonoids from Aristolochia contorta. Archives of Pharmacal How, F.C. 1985. A dictionary of the families and genera of Chinese Research 28, 1233–1235. seed plants, 2nd Ed., Science Press, Beijing, p. 43. Chen, Y.Y., Chiang, S.Y., Wu, H.C., Kao, S.T., Hsiang, C.Y., Ho, Hutchinson, J. 1973. The families of flowering plants, 3rd Ed., T.Y., Lin, J.G., 2010a. Microarray analysis reveals the inhibition Clarendon Press, Oxford, p. 510. of nuclear factor-kappa B signaling by aristolochic acid in normal Izquierdo, A.M., Zapata, E.V., Jiménez-Ferrer, J.E., Muñoz, C.B., human kidney (HK-2) cells. Acta Pharmacologica Sinica 31, 227– Aparicio, A.J., Torres, K.B., Torres, L.O., 2010. Scorpion 236. antivenom effect of micropropagated Aristolochia elegans . Chen, Y.Y., Chung, J.G., Wu, H.C., Bau, D.T., Wu, K.Y., Kao, S.T., Pharmaceutical Biology 48, 891–896. Hsiang, C.Y., Ho, T.Y., Chiang, S.Y., 2010b. Aristolochic acid Jbilou, R., Amri, H., Bouayad, N., Ghailani, N., Ennabili, A., suppresses DNA repair and triggers oxidative DNA damage in Sayah, F., 2008. Insecticidal effects of extracts of seven plant human kidney proximal tubular cells. Oncology Reports 24, 141– species on larval development, α-amylase activity and offspring 153. production of Tribolium castaneum (Herbst) (Insecta: Coleoptera: Chen, C.H., Dickman, K.G., Moriya, M., Zavadil, J., Sidorenko, Tenebrionidae). Bioresource Technology 99, 959–964. V.S., Edwards, K.L., Gnatenko, D.V., Wu, L., Turesky, R.J., Wu, Jiangsu New Medicine College. 1977. Encyclopedia of Chinese X.R., Pu, Y.S., Grollman, A.P., 2012. Aristolochic acid-associated materia medica, Vol. 1, Shanghai Science and Technology Press, urothelial cancer in Taiwan. Proceedings of the National Academy Shanghai, p. 294. of Sciences of the United States of America 109, 8241–8246. Jiménez-Ferrer, J.E., Pérez-Terán, Y.Y., Román-Ramos, R., Tortoriello, Chitme, H.R., Malipatil, M., Chandrashekhar, V.M., Prashant, P.M., J., 2005. Antitoxin activity of plants used in Mexican traditional 2010. Antiallergic activity of Aristolochia bracteolate Lank in medicine against scorpion poisoning. Phytomedicine 12, 116–122. animal model. Indian Journal of Experimental Biology 48, 46–52. Kamaraj, C., Rahuman, A.A., Mahapatra, A., Bagavan, A., Elango, Chung, Y.M., Chang, F.R., Tseng, T.F., Hwang, T.L., Chen, L.C., G., 2010. Insecticidal and larvicidal activities of medicinal plant Wu, S.F., Lee, C.L., Lin, Z.Y., Chuang, L.Y., Su, J.H., Wu, Y.C., extracts against mosquitoes. Parasitology Research 107, 1337– 2011. A novel alkaloid, aristopyridinone A and anti-inflammatory 1349. phenanthrenes isolated from Aristolochia manshuriensis . Kumar, V.P., Chauhan, N.S., Padh, H., Rajani, M., 2006. Search for Bioorganic & Medicinal Chemistry Letters 21, 1792–1794. antibacterial and antifungal agents from selected Indian medicinal Correa, M.P. 1978. Dicionario das plantas uteis do Brasil e das plants. Journal of Ethnopharmacology 107, 182–188. exoticas cultivadas, Vols. 1-2, Imprensa Nacional, Rio de Janeiro, León-Díaz, R., Meckes, M., Said-Fernández, S., Molina-Salinas, pp. 1926–1978. G.M., Vargas-Villarreal, J., Torres, J., Luna-Herrera, J., Jiménez- Cosyns, J.P., 2003. Aristolochic acid and 'Chinese herbs nephropathy': Arellanes, A., 2010. Antimycobacterial neolignans isolated from a review of the evidence to date. Drug Safety 26, 33–48. Aristolochia taliscana. Memórias do Instituto Oswaldo Cruz, Rio de Barros Machado, T., Leal, I.C.R., Kuster, R.M., Amaral, A.C.F., de Janeiro 105, 45–51. Kokis, V., de Silva, M.G., dos Santos, K.R.N., 2005. Brazilian Li, S.Z. 1977. Ban Tso Gan Mo, Peoples Health Press, Beijing, p. phytopharmaceuticals – evaluation against hospital bacteria. 1595. Phytotherapy Research 19, 519–525. Liu, T.S., and Lai, M.J. 1976. Flora of Taiwan, Vol. 2, Epoch, Taipei, de Pascoli, I.C., Nascimento, I.R., Lopes, L.M.X., 2006. p. 572. Configurational analysis of cubebins and bicubebin from Lopes, L.M.X., Nascimento, I.R., and Da Silva, T. 2001. Aristolochia lagesiana and Aristolochia pubescens. Phytochemistry Phytochemistry of the Aristolochiaceae family, in: Mohan, R.M.M. 67, 735–742. ed., Research advances in phytochemistry, Vol. 2, Global Research Duke, J.A. 1985. CRC handbook of medicinal herbs, CRC Press, Boca Network, Kerala, pp. 19–108. Raton, FL, p. 63. Machado, M.B., Lopes, L.M.X., 2005. Chalcone-flavone tetramer and Duke, J.A, and Ayensu, E.S. 1985. Medicinal plants of China, Vol. 1, biflavones fromAristolochia ridicula. Phytochemistry 66, 669–674. Reference Publications Inc., Algonac, MI, p. 131. Machado, M.B., Lopes, L.M.X., 2008. Tetraflavonoid and biflavonoids Elango, G., Rahuman, A.A., Kamaraj, C., Bagavan, A., Zahir, A.A., from Aristolochia ridicula. Phytochemistry 69, 3095–3102. 2011. Screening for feeding deterrent activity of herbal extracts Messiano, G.B., Vieira, L., Machado, M.B., Lopes, L.M.X., de against the larvae of malaria vector Anopheles subpictus Grassi. Bortoli, S.A., Zukerman-Schpector, J., 2008. Evaluation of Parasitology Research 109, 715–726. insecticidal activity of diterpenes and lignans from Aristolochia Ferreira, M.L.R., de Pascoli, I.C., Nascimento, I.R., Zukerman- malmeana against Anticarsia gemmatalis. Journal of Agricultural Schpector, J., Lopes, L.M.X., 2010. Aporphine and bisaporphine and Food Chemistry 56, 2655–2659. alkaloids from Aristolochia lagesiana var. intermedia . Nascimento, I.R., Murata, A.T., Bortoli, S.A., Lopes, L.M.X., 2003. Phytochemistry 71, 469–478. Insecticidal activity of chemical constituents from Aristolochia Georgopoulou, C., Aligiannis, N., Fokialakis, N., Mitaku, S., 2005. pubescens against Anticarsia gemmatalis larvae. Pest Management

265 Kuo et al. / Journal of Traditional and Complementary Medicine 2 (2012) 249-266

Science 60, 413–416. pollen. Plant Physiology 100, 902–907. Navarro-García, V.M., Luna-Herrera, J., Rojas-Bribiesca, M.G., Yu, J.Q., Liao, Z.X., Cai, X.Q., Lei, J.C., Zou, G.L., 2007. Álvarez-Fitz, P., Ríos, M.Y., 2011. Antibacterial activity of Composition, antimicrobial activity and cytotoxicity of essential Aristolochia brevipes against multidrug-resistant Mycobacterium oils from Aristolochia mollissima. Environmental Toxicology and tuberculosis. Molecules 16, 7357–7364. Pharmacology 23, 162–167. Nedelko, T., Arlt, V.M., Phillips, D.H., Hollstein, M., 2009. TP53 Zhai, H., Nakatsukasa, M., Mitsumoto, Y., Fukuyama, Y., 2004. mutation signature supports involvement of aristolochic acid Neurotrophic effects of talaumidin, a neolignan from Aristolochia in the aetiology of endemic nephropathy-associated tumours. arcuata, in primary cultured rat cortical neurons. Planta Medica 70, International Journal of Cancer 124, 987–990. 598–602. Nok, A.J., Sallau, B.A., Onyike, E., Useh, N.M., 2005. Columbin Zhai, H., Inoue, T., Moriyama, M., Esumi, T., Mitsumoto, Y., inhibits cholesterol uptake in bloodstream forms of Trypanosoma Fukuyama, Y., 2005. Neuroprotective effects of 2,5-diaryl-3,4- brucei − A possible trypanocidal mechanism. Journal of Enzyme dimethyltetrahydrofuran neolignans. Biological and Pharmaceutical Inhibition and Medicinal Chemistry 20, 365–368. Bulletin 28, 289–293. Nortier, J.L., Martinez, M.C.M., Schmeiser, H.H., Arlt, V.M., Bieler, Zhang, G., Shimokawa, S., Mochizuki, M., Kumamoto, T., Nakanishi, C.A., Petein, M., Depierreux, M.F., Pauw, L.D., Abramowicz, D., W., Watanabe, T., Ishikawa, T., Matsumoto, K., Tashima, K., Horie, Vereerstraeten, P., Vanherweghem, J.L., 2000. Urothelial carcinoma S., Higuchi, Y., Dominguez, O.P., 2008. Chemical constituents of associated with the use of a Chinese herb (Aristolochia fangchi). Aristolochia constricta: antispasmodic effects of its constituents The New England Journal of Medicine 342, 1686–1692. in guinea-pig ileum and isolation of a diterpeno−lignan hybrid. Perry, L.M. 1980. Medicinal plants of the East and Southeast Asia, Journal of Natural Products 71, 1167–1172. MIT press, Cambridge. Zhu, S., Sunnassee, A., Yuan, R., Ren, L., Chen, X., Liu, L., 2010. Pharmacopoeia of the People’s Republic of China, 1977. English Fatal renal failure due to the Chinese herb ‘‘GuanMuTong’’ Edition, The Pharmacopeia Commission of PROC, Beijing. (Aristolochia manshuriensis): Autopsy findings and review of Pharmacopeia of China, Vol. 1, 1985. Peoples Press, Beijing, pp. 36– literature. Forensic Science International 199, e5–e7. 38. Romeo, J., Downum, K., and Verpoorte, R. 1998. Recent advances in phytochemistry, Plenum Publication, New York. Samy, R.P., Thwin, M.M., Gopalakrishnakone, P., Ignacimuthu, S., 2008. Ethnobotanical survey of folk plants for the treatment of snakebites in Southern part of Tamilnadu, India. Journal of Ethnopharmacology 115, 302–312. Sartorelli, P., Carvalho, C.S., Reimão, J.Q., Lorenzi, H., Tempone, A.G., 2010. Antitrypanosomal activity of diterpene and lignans isolated from Aristolochia cymbifera. Planta Medica 76, 1454– 1456. Shen, M.Y., Liu, C.L., Hsiao, G., Liu, C.Y., Lin, K.H., Chou, D.S., Sheu, J.R., 2008. Involvement of p38 MAPK phosphorylation and nitrate formation in aristolochic acid-mediated antiplatelet activity. Planta Medica 74, 1240–1245. Shi, L.S., Kuo, P.C., Tsai, Y.L., Damu, A.G., Wu, T.S., 2004. The alkaloids and other constituents from the root and stem of Aristolochia elegans. Bioorganic & Medicinal Chemistry 12, 439– 446. Simoes, C.M.O., Mentz, L.A., Schenkel, E.P., Iragang, B.E., and Stehmann, J.R. 1986. Plants da Medicina Popular no Rio Grande do Sul, UFRGS Ed, Porto Alegre, p. 50. Stafford, H.A., 1997. Roles of flavonoids in symbiotic and defense functions in legume roots. The Botanical Review 63, 27–39. Tang, W., and Eisenbrand, G. 1992. Chinese drug of plant origin chemistry, pharmacology and use in traditional and modern medicine, Springer-Verlag, Berlin, p. 145. The European Agency for the Evaluation of Medicinal Products, 1997, Veterinary Medicines Evaluation unit, London. Therapuetic Goods Administration, 2001. Practitioner alert, Commonwealth department of Health and Aged care, Australia. Vanherweghem, J.L., Depierreux, M., Tielemans, C., Abramowicz, D., Dratwa, M., Jadoul, M., Richard, C., Vandervelde, D., Verbeelen, D., Vanhaelen-Faster, R., Vanhealen, M., 1993. Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs. Lancet 431, 387–391. Vanherweghem, J.L., 2002. Chinese herbs (Aristolochia) nephropathy. Nieren-und Hochdruckkrankheiten 31, 344–349. Watson, L., and Dallwitz, M.J. 1992. The families of flowering plants, CSIRO Publicatoins, Melbourne. Wu, T.S., Damu, A.G., Su, C.R., and Kuo, P.C. 2005. Chemical constituents and pharmacology of Aristolochia Species, in: Atta- ur-Rahman, ed., Studies in natural product chemistry (bioactive natural proudcts), Vol. 32, Elsevier, Amsterdam, pp. 855–1018. Ylstra, B., Touraev, A., Moreno, R.M.B., Stöger, E., van Tunen, A.J., Vicente, O., Mol, J.N.M., Heberle-Bors, E., 1992. Flavonols stimulate development, germination, and tube growth of tobacco

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